MEDICAMENT COMPRISING COMBINATION OF SEPETAPROST AND Rho-ASSOCIATED COILED-COIL CONTAINING PROTEIN KINASE INHIBITOR

ABSTRACT

Described is a combination of a prophylactic or therapeutic agent for glaucoma or ocular hypertension, which is useful as a prophylactic or therapeutic agent for glaucoma or ocular hypertension. By combining sepetaprost and a Rho-associated coiled-coil containing protein kinase inhibitor(s), an intraocular pressure lowering action is enhanced as compared with the case where each drug is used alone. As the form of administration, they may be administered concomitantly or may be administered as a combination drug.

TECHNICAL FIELD

The present invention relates to a prophylactic or therapeutic agent forglaucoma or ocular hypertension, which is characterized in thatsepetaprost and a Rho-associated coiled-coil containing protein kinaseinhibitor(s) are administered in combination. The present invention alsorelates to a prophylactic or therapeutic agent for glaucoma or ocularhypertension comprising sepetaprost, which is characterized by beingused concomitantly with a Rho-associated coiled-coil containing proteinkinase inhibitor(s).

BACKGROUND ART

Glaucoma is a refractory eye disease caused by suffering from damage ofthe internal tissue (retina, optic nerve, etc.) of the eyeball due tothe intraocular pressure increases resulted from various pathogenesis.As a method for treating glaucoma, intraocular pressure lowering therapyis generally used, and typical examples thereof include drug therapy,laser therapy, surgical therapy, etc.

In the drug therapy, drugs such as sympathomimetics (non-selectivestimulants such as dipivefrin, etc., and α₂ receptor agonists such asbrimonidine, etc.), sympathetic nerve blockers (β receptor blockers suchas timolol, befunolol, carteolol, nipradilol, betaxolol, levobunolol,metipranolol, etc., and α₁ receptor blockers such as bunazosinhydrochloride, etc.), parasympathomimetics (pilocarpine, etc.), carbonicanhydrase inhibitors (acetazolamide, etc.), prostaglandins (isopropylunoprostone, latanoprost, travoprost, bimatoprost, etc.), andRho-associated coiled-coil containing protein kinase inhibitors(ripasudil), etc., have been used.

Also, in order to obtain a more potent effect of lowering an intraocularpressure, some reports have been made that drugs having an intraocularpressure lowering effect are used in combination. For example, in JPPatent No. 2,726,672 (Patent Document 2), administration of acombination of a sympathetic nerve blocker and a prostaglandin has beenreported. Also, in WO 2002/38158 (Patent Document 3), a therapeuticmethod for glaucoma by administering several drugs having an intraocularpressure lowering action in combination to the eye has been disclosed.Further, in WO 2004/019951 (Patent Document 4), administration of acombination of a Rho-associated coiled-coil containing protein kinaseinhibitor and a prostaglandin has been reported, and in WO 2004/045644(Patent Document 5), combination administration of a Rho-associatedcoiled-coil containing protein kinase inhibitor and a β receptor blockerhas been reported. In addition, a combination drug of dorzolamide andtimolol, a combination drug of latanoprost and timolol, a combinationdrug of brimonidine and timolol and the like are commercially available(Non-Patent Document 1).

By the way, sepetaprost is the compound represented by the formula (1):

and described in Patent Document 6 as one of the huge number of thecompounds. Since these compounds have a potent and sustained intraocularpressure lowering action, there are described that they are expected tobe a therapeutic agent for glaucoma.

PRIOR ART DOCUMENTS Patent Documents

-   Patent Document 1: WO 2010/113957-   Patent Document 2: JP Patent No. 2,726,672-   Patent Document 3: WO 2002/38158-   Patent Document 4: WO 2004/019951-   Patent Document 5: WO 2004/045644-   Patent Document 6: WO 2011/013651

Non-Patent Documents

-   Non-Patent Document 1: Clinical Ophthalmology, 2010, 4, 1-9

SUMMARY OF THE INVENTION Problems to be Solved by the Invention

It is a very interesting task to find out a combination of prophylacticor therapeutic agents for glaucoma or ocular hypertension, which isuseful as a prophylactic or therapeutic agent for glaucoma or ocularhypertension.

Means for Solving the Problems

The present inventors have intensively studied the effect of thecombination of prophylactic or therapeutic agents for glaucoma or ocularhypertension, and as a result, they have found that by using sepetaprostand a Rho-associated coiled-coil containing protein kinase inhibitor(s)in combination, an intraocular pressure lowering action is enhanced ascompared with the case where each drug is used alone, whereby they haveaccomplished the present invention.

That is, the present invention relates to the following.

(1) A prophylactic or therapeutic agent for glaucoma or ocularhypertension which is characterized in that sepetaprost and aRho-associated coiled-coil containing protein kinase inhibitor(s) areadministered in combination.

(2) The prophylactic or therapeutic agent described in theabove-mentioned (1), which is a combination drug comprising sepetaprostand the Rho-associated coiled-coil containing protein kinaseinhibitor(s).

(3) The prophylactic or therapeutic agent described in theabove-mentioned (1), wherein sepetaprost and the Rho-associatedcoiled-coil containing protein kinase inhibitor(s) are administered atdifferent times or simultaneously.

(4) A prophylactic or therapeutic agent for glaucoma or ocularhypertension comprising sepetaprost, which is characterized by beingused concomitantly with a Rho-associated coiled-coil containing proteinkinase inhibitor(s).

(5) The prophylactic or therapeutic agent described in theabove-mentioned (4), which is administered at different time from orsimultaneously with the Rho-associated coiled-coil containing proteinkinase inhibitor(s).

(6) The prophylactic or therapeutic agent described in any one of theabove-mentioned (1) to (5), wherein the Rho-associated coiled-coilcontaining protein kinase(s) inhibitor is at least one kind selectedfrom the group consisting of ripasudil, netarsudil and a salt thereof.

(7) The prophylactic or therapeutic agent described in any one of theabove-mentioned (1) to (6), wherein the Rho-associated coiled-coilcontaining protein kinase inhibitor(s) is ripasudil monohydrochloridedihydrate.

(8) The prophylactic or therapeutic agent described in any one of theabove-mentioned (1) to (6), wherein the Rho-associated coiled-coilcontaining protein kinase inhibitor(s) is dimesylate or dihydrochlorideof netarsudil.

Also, the present invention relates to the following.

(9) An intraocular pressure-lowering agent, which is characterized inthat sepetaprost and a Rho-associated coiled-coil containing proteinkinase inhibitor(s) are combined.

(10) An intraocular pressure-lowering agent comprising sepetaprost,which is characterized by being used concomitantly with a Rho-associatedcoiled-coil containing protein kinase inhibitor(s).

Further, the present invention relates to the following.

(11) A prophylactic or therapeutic composition for glaucoma or ocularhypertension comprising sepetaprost, which is characterized by beingadministered in combination with a Rho-associated coiled-coil containingprotein kinase inhibitor(s).

(12) A prophylactic or therapeutic method for glaucoma or ocularhypertension comprising: administering a therapeutically effectiveamount of sepetaprost and a therapeutically effective amount of aRho-associated coiled-coil containing protein kinase inhibitor(s) to asubject in need thereof.

(13) Use of a combination of sepetaprost and a Rho-associatedcoiled-coil containing protein kinase inhibitor(s) for manufacturing amedicament for the prophylaxis or treatment for glaucoma or ocularhypertension.

(14) Use of sepetaprost for manufacturing a medicament for theprophylaxis or treatment for glaucoma or ocular hypertensioncharacterized by being used concomitantly with a Rho-associatedcoiled-coil containing protein kinase inhibitor(s).

(15) Sepetaprost for use in the prophylaxis or treatment for glaucoma orocular hypertension, which is characterized by being used concomitantlywith a Rho-associated coiled-coil containing protein kinaseinhibitor(s).

(16) A combination of sepetaprost and a Rho-associated coiled-coilcontaining protein kinase inhibitor(s) for use in the prophylaxis ortreatment for glaucoma or ocular hypertension.

Moreover, the present invention relates to the following.

(17) A composition for lowering an intraocular pressure comprisingsepetaprost, which is characterized by being administered in combinationwith a Rho-associated coiled-coil containing protein kinaseinhibitor(s).

(18) A method for lowering an intraocular pressure comprising:administering a therapeutically effective amount of sepetaprost and atherapeutically effective amount of a Rho-associated coiled-coilcontaining protein kinase inhibitor(s) to a subject in need thereof.

(19) Use of a combination of sepetaprost and a Rho-associatedcoiled-coil containing protein kinase inhibitor(s) for manufacturing amedicament for lowering an intraocular pressure.

(20) Use of sepetaprost for manufacturing a medicament for lowering anintraocular pressure characterized by being used concomitantly with aRho-associated coiled-coil containing protein kinase inhibitor(s).

(21) Sepetaprost for use in lowering an intraocular pressure, which ischaracterized by being used concomitantly with a Rho-associatedcoiled-coil containing protein kinase inhibitor(s).

(22) A combination of sepetaprost and a Rho-associated coiled-coilcontaining protein kinase inhibitor(s) for use in lowering anintraocular pressure.

Incidentally, each constitution of the above-mentioned (1) to (22) canbe combined by arbitrary selecting two or more.

Effects of the Invention

By administering sepetaprost and a Rho-associated coiled-coil containingprotein kinase inhibitor(s) to an eye in combination, an intraocularpressure lowering action is enhanced. Accordingly, the present inventionis useful as a prophylactic or therapeutic agent for glaucoma or ocularhypertension. Further, according to the present invention, sufficientsafety as a pharmaceutical product is ensured.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing change in the lowering width of an intraocularpressure with the lapse of time for each administered group ofsepetaprost and ripasudil alone, and concomitant use.

FIG. 2 is a graph showing change in the lowering width of an intraocularpressure with the lapse of time for each administered group ofsepetaprost and netarsudil alone, and concomitant use.

DESCRIPTION OF THE EMBODIMENTS

In the following, the present invention will be explained in detail.

The present invention is directed to a prophylactic or therapeutic agentfor glaucoma or ocular hypertension, which is characterized in thatsepetaprost and a Rho-associated coiled-coil containing protein kinaseinhibitor(s) are administered in combination, and hereinafter, these arealso simply referred to as the “therapeutic agent or the like”.

In the therapeutic agent or the like of the present invention,sepetaprost is the compound (CAS registry number: 1262873-06-2)represented by the following formula (1):

and is also referred to as 2-propanyl4-{(3S,5aR,6R,7R,8aS)-6-[(1E,3R)-4-(2,5-difluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate.

Sepetaprost can be produced in accordance with the methods disclosed inWO 2011/013651 (Patent Document 6), or a usual method in this technicalfield.

When there are geometric isomers and/or optical isomers in sepetaprost,those isomers are also included in the scope of the present invention.

When there is proton tautomerism in sepetaprost, those tautomers (ketoform and enol form) are also included in the scope of the presentinvention.

When there is crystal polymorphism and/or crystal polymorph group(crystal polymorph system) in sepetaprost, those crystal polymorphsand/or crystal polymorph group (crystal polymorph system) are alsoincluded in the scope of the present invention. Here, the crystalpolymorph group (crystal polymorph system) means a crystal form at eachstage when the crystal form changes to various crystal forms dependingon the conditions and/or states (incidentally, in this state, aformulated state is also included) of production, crystallization andpreservation of these crystals, and/or the whole thereof.

Sepetaprost may take a form of a hydrate or a solvate.

In the therapeutic agent or the like of the present invention, a contentof sepetaprost is not particularly limited, which may vary depending onthe administration form, and in the case of eye drops, a lower limit ofthe content of sepetaprost is preferably 0.000001 to 5% (w/v), and morepreferably 0.00001 to 0.05% (w/v). Here, “% (w/v)” means a mass (g) ofan active ingredient(s) or an additive(s) contained in 100 mL of thedrug. For example, 0.01% (w/v) sepetaprost means that the content ofsepetaprost contained in 100 mL of the drug is 0.01 g.

Incidentally, when sepetaprost is in the form of a hydrate or a solvate,the content of sepetaprost may be calculated based on any of a freeform, a hydrate or a solvate of sepetaprost.

The Rho-associated coiled-coil containing protein kinase inhibitor(s) inthe therapeutic agent or the like of the present invention means acompound which inhibits a serine/threonine kinase activated accompaniedby activation of Rho. For example, there may be mentioned ROKα(ROCK-II), p160ROCK (ROKβ, ROCK-I) and other compounds which inhibit aprotein having a serine/threonine kinase activity.

As specific examples of the Rho-associated coiled-coil containingprotein kinase inhibitor(s), a Rho-associated coiled-coil containingprotein kinase inhibitor such as(R)-trans-N-(pyridin-4-yl)-4-(1-aminoethyl)cyclohexanecarboxamide,(R)-(+)-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-aminoethyl)benzamide orthe like disclosed in WO 98/06433 and WO 00/09162; a Rho-associatedcoiled-coil containing protein kinase inhibitor such as1-(5-isoquinolinesulfonyl)homopiperazine,1-(5-isoquinolinesulfonyl)-2-methylpiperazine or the like disclosed inWO 97/23222 and Nature, 389, 990-994 (1997); a Rho-associatedcoiled-coil containing protein kinase inhibitor such as(1-benzylpyrrolidin-3-yl)-(1H-indazol-5-yl)amine or the like disclosedin WO 01/56988; a Rho-associated coiled-coil containing protein kinaseinhibitor such as (1-benzylpiperidin-4-yl)-(1H-indazol-5-yl)amine or thelike disclosed in WO 02/100833; a Rho-associated coiled-coil containingprotein kinase inhibitor such asN-[2-(4-fluorophenyl)-6,7-dimethoxy-4-quinazolinyl]-N-(1H-indazol-5-yl)amineor the like disclosed in WO 02/076976; a Rho-associated coiled-coilcontaining protein kinase inhibitor such asN-4-(1H-indazol-5-yl)-6,7-dimethoxy-N-2-pyridin-4-yl-quinazoline-2,4-diamineor the like disclosed in WO 02/076977; a Rho-associated coiled-coilcontaining protein kinase inhibitor such as4-methyl-5-(2-methyl-[1,4]diazepane-1-sulfonyl)isoquinoline or the likedisclosed in WO 99/64011; a Rho-associated coiled-coil containingprotein kinase inhibitor such as(S)-(−)-1-(4-fluoro-5-isoquinolinesulfonyl)-2-methyl-1,4-homopiperazineor the like disclosed in WO 2006/068208; and a Rho-associatedcoiled-coil containing protein kinase inhibitor such as4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl2,4-dimethylbenzoate or the like disclosed in WO 2010/126626 areexemplified. Among these, in particular,(S)-(−)-1-(4-fluoro-5-isoquinolinesulfonyl)-2-methyl-1,4-homopiperazine,4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl2,4-dimethylbenzoate and[4-[(1S)-1-(aminomethyl)-2-(isoquinolin-6-ylamino)-2-oxoethyl]phenyl]methyl2,4-dimethylbenzoate are preferred.

In the therapeutic agent or the like of the present invention, a contentof the Rho-associated coiled-coil containing protein kinase inhibitor(s)is not particularly limited, which may vary depending on theadministration form, and in the case of eye drops, a content of theRho-associated coiled-coil containing protein kinase inhibitor(s) ispreferably 0.0001 to 5% (w/v), and more preferably 0.001 to 1% (w/v).

Incidentally, when the Rho-associated coiled-coil containing proteinkinase inhibitor(s) is in the form of a salt, a hydrate or a solvate,the contents of these Rho-associated coiled-coil containing proteinkinase inhibitor(s) may be calculated based on any of a free form, asalt, a hydrate or a solvate of the Rho-associated coiled-coilcontaining protein kinase inhibitor(s).

In the therapeutic agent or the like of the present invention, ripasudilis the compound (CAS registry number: 223645-67-8) represented by thefollowing formula (2)

which is also referred to as(S)-(−)-1-(4-fluoro-5-isoquinolinesulfonyl)-2-methyl-1,4-homopiperazine.Since it has a Rho-associated coiled-coil containing protein kinaseinhibitory action, and promotes drainage of aqueous humor from the mainoutflow passage via travecula-Schlemm's canal, it has been sold as atherapeutic agent for glaucoma and ocular hypertension (Glanatec(Registered Trademark) eye drops 0.4%).

In the therapeutic agent or the like of the present invention, the saltof ripasudil is not particularly limited as long as it is apharmacologically acceptable salt. Specific examples include aninorganic acid salt such as hydrochloride, hydrobromide, hydroiodide,nitrate, sulfate or phosphate; an organic acid salt such as acetate,trifluoroacetate, benzoate, oxalate, malonate, succinate, maleate,fumarate, tartrate, citrate, methanesulfonate, ethanesulfonate,trifluoromethanesulfonate, benzenesulfonate, p-toluenesulfonate,glutamate or aspartate; a metal salt such as sodium salt, potassiumsalt, calcium salt or magnesium salt; an inorganic salt such as ammoniumsalt; or an organic amine salt such as triethylamine salt or guanidinesalt, preferably hydrochloride, and further preferablymonohydrochloride.

When there are geometric isomers and/or optical isomers in ripasudil ora salt thereof, those isomers are also included in the scope of thepresent invention.

When there is proton tautomerism in ripasudil or a salt thereof, thosetautomers (keto form and enol form) are also included in the scope ofthe present invention.

When there is crystal polymorphism and/or crystal polymorph group(crystal polymorph system) in ripasudil or a salt thereof, those crystalpolymorphs and/or crystal polymorph group (crystal polymorph system) arealso included in the scope of the present invention. Here, the crystalpolymorph group (crystal polymorph system) means a crystal form at eachstage when the crystal form changes to various crystal forms dependingon the conditions and/or states (incidentally, in this state, aformulated state is also included) of production, crystallization andpreservation of these crystals, and/or the whole thereof.

In the therapeutic agent or the like of the present invention, ripasudilor a salt thereof may take a form of a hydrate or a solvate. As the saltand hydrate of ripasudil, ripasudil monohydrochloride dihydrate (CASregistry number; 887375-67-9) is most preferable. In the therapeuticagent or the like of the present invention, ripasudil or a salt thereof,or a hydrate or a solvate thereof is also simply referred to as“ripasudil”.

In the therapeutic agent or the like of the present invention, a contentof ripasudil or a salt thereof is not particularly limited, which mayvary depending on the administration form, and in the case of eye drops,a lower limit of the content of ripasudil or a salt thereof ispreferably 0.01% (w/v), more preferably 0.05% (w/v), further preferably0.1% (w/v), and particularly preferably 0.2% (w/v). Also, an upper limitof the above-mentioned content is preferably 3% (w/v), more preferably2% (w/v), further preferably 1% (w/v), and particularly preferably 0.6%(w/v). In more detail, the above-mentioned content may be a range inwhich any of the above-mentioned lower limit and upper limit arecombined, and preferably 0.01 to 3% (w/v), more preferably 0.05 to 2%(w/v), further preferably 0.1 to 1% (w/v), particularly preferably 0.2to 0.6% (w/v), and most preferably 0.4% (w/v).

Incidentally, when ripasudil or a salt thereof is in the form of a salt,the contents of these ripasudil or a salt thereof may be calculatedbased on any of a free form, a salt, a hydrate or a solvate of ripasudilor a salt thereof.

In the therapeutic agent or the like of the present invention,netarsudil is the compound (CAS registry number: 1254032-66-0)represented by the following formula (3):

which is also referred to as[4-[(1S)-1-(aminomethyl)-2-(isoquinolin-6-ylamino)-2-oxoethyl]phenyl]methyl2,4-dimethylbenzoate. Since it has a Rho-associated coiled-coilcontaining protein kinase inhibitory action and a norepinephrinetransporter (NEP) inhibitory action, and exhibits an intraocularpressure lowering action, it has been sold as a therapeutic agent forglaucoma and ocular hypertension in the United States (RHOPRESSA(Registered Trademark) 0.02%).

In the therapeutic agent or the like of the present invention, the saltof netarsudil is not particularly limited as long as it is apharmacologically acceptable salt. Specific examples include aninorganic acid salt such as hydrochloride, hydrobromide, hydroiodide,nitrate, sulfate or phosphate; an organic acid salt such as acetate,trifluoroacetate, benzoate, oxalate, malonate, succinate, maleate,fumarate, tartrate, citrate, mesylate (methanesulfonate),ethanesulfonate, trifluoromethanesulfonate, benzenesulfonate,p-toluenesulfonate, glutamate or aspartate; a metal salt such as sodiumsalt, potassium salt, calcium salt or magnesium salt; an inorganic saltsuch as ammonium salt; or an organic amine salt such as triethylaminesalt or guanidine salt, preferably mesylate (methanesulfonate) orhydrochloride, and more preferably dimesylate (dimethanesulfonate) ordihydrochloride.

When there are geometric isomers and/or optical isomers in netarsudil ora salt thereof, those isomers are also included in the scope of thepresent invention.

When there is proton tautomerism in netarsudil or a salt thereof, thosetautomers (keto form and enol form) are also included in the scope ofthe present invention.

When there is crystal polymorphism and/or crystal polymorph group(crystal polymorph system) in netarsudil or a salt thereof, thosecrystal polymorphs and/or crystal polymorph group (crystal polymorphsystem) are also included in the scope of the present invention. Here,the crystal polymorph group (crystal polymorph system) means a crystalform at each stage when the crystal form changes to various crystalforms depending on the conditions and/or states (incidentally, in thisstate, a formulated state is also included) of production,crystallization and preservation of these crystals, and/or the wholethereof.

In the therapeutic agent or the like of the present invention,netarsudil or a salt thereof may take a form of a hydrate or a solvate.As the salt and hydrate of netarsudil, netarsudil dimesylate (CASregistry number: 1422144-42-0) is most preferable. In the therapeuticagent or the like of the present invention, netarsudil or a saltthereof, or a hydrate or a solvate thereof is also simply referred to as“netarsudil”.

In the therapeutic agent or the like of the present invention, a contentof netarsudil or a salt thereof is not particularly limited, which mayvary depending on the administration form, and in the case of eye drops,a lower limit of the content of netarsudil or a salt thereof ispreferably 0.001% (w/v), more preferably 0.003% (w/v), furtherpreferably 0.005% (w/v), and particularly preferably 0.01% (w/v). Also,an upper limit of the above-mentioned content is preferably 0.2% (w/v),more preferably 0.1% (w/v), further preferably 0.06% (w/v), andparticularly preferably 0.04% (w/v). In more detail, the above-mentionedcontent may be a range in which any of the above-mentioned lower limitand upper limit are combined, and preferably 0.001 to 0.2% (w/v), morepreferably 0.003 to 0.1% (w/v), further preferably 0.005 to 0.06% (w/v),particularly preferably 0.01 to 0.04% (w/v), and most preferably 0.02%(w/v).

Incidentally, when netarsudil or a salt thereof is in the form of asalt, a hydrate or a solvate, the contents of these netarsudil or a saltthereof may be calculated based on any of a free form, a salt, a hydrateor a solvate of netarsudil or a salt thereof.

In the therapeutic agent or the like of the present invention, inaddition to sepetaprost and the Rho-associated coiled-coil containingprotein kinase inhibitor(s), one or more of the other prophylactic ortherapeutic agent(s) for glaucoma or ocular hypertension may be furtherused in combination. The other prophylactic or therapeutic agent(s) forglaucoma or ocular hypertension may be any drug as long as it has anintraocular pressure lowering action and is useful for the treatment forglaucoma, and there may be mentioned non-selective sympathomimetics, α₂receptor agonists, α₁ receptor blockers, β receptor blockers,parasympathomimetics, carbonic anhydrase inhibitors, prostaglandins andthe like.

Specific examples of the non-selective sympathomimetics includedipivefrin, specific examples of the α₂ receptor agonists includebrimonidine and apraclonidine, specific examples of the α₁ receptorblockers include bunazosin, specific examples of the β receptor blockersinclude timolol, befunolol, carteolol, nipradilol, betaxolol,levobunolol and metipranolol, specific examples of theparasympathomimetics include pilocarpine, specific examples of thecarbonic anhydrase inhibitors include dorzolamide, brinzolamide andacetazolamide, and specific examples of the prostaglandins includeisopropyl unoprostone, latanoprost, travoprost and bimatoprost. Theseinclude a form of a salt pharmaceutically acceptable as a medicine.Specific examples of the salt include an inorganic acid salt such ashydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or phosphate;an organic acid salt such as acetate, trifluoroacetate, benzoate,oxalate, malonate, succinate, maleate, fumarate, tartrate, citrate,methanesulfonate, ethanesulfonate, trifluoromethanesulfonate,benzenesulfonate, p-toluenesulfonate, glutamate or aspartate; a metalsalt such as sodium salt, potassium salt, calcium salt or magnesiumsalt; an inorganic salt such as ammonium salt; or an organic amine saltsuch as triethylamine salt or guanidine salt.

Further, the other prophylactic or therapeutic agent(s) for glaucoma orocular hypertension may take a form of a hydrate or a solvate.

In the therapeutic agent or the like of the present invention, when itis used in combination with the other prophylactic or therapeuticagent(s) for glaucoma or ocular hypertension, a content thereof is notparticularly limited, which may vary depending on a kind and anadministration form of the prophylactic or therapeutic agent to becontained, and a preferred content in the case of eye drops is asfollows.

The content of the non-selective sympathomimetics may vary depending ona kind of the drug, and in the case of dipivefrin, it is preferably0.001 to 3% (w/v), more preferably 0.04 to 0.1% (w/v), and particularlypreferably 0.04% (w/v) or 0.1% (w/v).

The content of the α₂ receptor agonists may vary depending on a kind ofthe drug, and in the case of brimonidine, it is preferably 0.01 to 5%(w/v), more preferably 0.1 to 0.5% (w/v), and particularly preferably0.1% (w/v), 0.15% (w/v), 0.2% (w/v) or 0.5% (w/v). Also, in the case ofapraclonidine, it is preferably 0.01 to 5% (w/v), more preferably 0.5 to1% (w/v), and particularly preferably 0.5% (w/v).

The content of the α₁ receptor blockers may vary depending on a kind ofthe drug, and in the case of bunazosin, it is preferably 0.001 to 0.3%(w/v), more preferably 0.003 to 0.03% (w/v), and particularly preferably0.01% (w/v).

The content of the β receptor blockers may vary depending on a kind ofthe drug, and in the case of timolol, it is preferably 0.01 to 5% (w/v),more preferably 0.1 to 0.5% (w/v), and particularly preferably 0.1%(w/v), 0.25% (w/v) or 0.5% (w/v). Also, in the case of befunolol, it ispreferably 0.01 to 5% (w/v), more preferably 0.25 to 1% (w/v), andparticularly preferably 0.25% (w/v), 0.5% (w/v) or 1% (w/v). In the caseof carteolol, it is preferably 0.01 to 5% (w/v), more preferably 1 to 2%(w/v), and particularly preferably 1% (w/v) or 2% (w/v). In the case ofnipradilol, it is preferably 0.01 to 5% (w/v), and particularlypreferably 0.25% (w/v). In the case of betaxolol, it is preferably 0.01to 5% (w/v), more preferably 0.25 to 0.5% (w/v), and particularlypreferably 0.25% (w/v) or 0.5% (w/v). In the case of levobunolol, it ispreferably 0.01 to 5% (w/v), more preferably 0.25 to 0.5% (w/v), andparticularly preferably 0.25% (w/v) or 0.5% (w/v). In the case ofmetipranolol, it is preferably 0.01 to 5% (w/v), and particularlypreferably 0.3% (w/v).

The content of the parasympathomimetics may vary depending on a kind ofthe drug, and in the case of pilocarpine, it is preferably 0.01 to 20%(w/v), more preferably 0.1 to 5% (w/v), and particularly preferably 0.5%(w/v), 1% (w/v), 2% (w/v), 3% (w/v) or 4% (w/v).

The content of the carbonic anhydrase inhibitors may vary depending on akind of the drug, and in the case of dorzolamide, it is preferably 0.01to 5% (w/v), more preferably 0.5 to 2% (w/v), and particularlypreferably 0.5% (w/v), 1% (w/v) or 2% (w/v). Also, in the case ofbrinzolamide, it is preferably 0.01 to 5% (w/v), more preferably 0.1 to2% (w/v), and particularly preferably 1% (w/v). Also, in the case ofacetazolamide, it is preferably 0.01 to 5% (w/v), and more preferably 1to 5% (w/v). Incidentally, when acetazolamide is orally administered,250 to 1000 mg may be used as a daily dose.

The content of the prostaglandins may vary depending on a kind of thedrug, and in the case of latanoprost, it is preferably 0.0001 to 5%(w/v), more preferably 0.0005 to 1% (w/v), further preferably 0.001 to0.1% (w/v), and particularly preferably 0.005% (w/v). In the case ofisopropyl unoprostone, it is preferably 0.001 to 5% (w/v), morepreferably 0.01 to 1% (w/v), further preferably 0.12 to 0.15% (w/v), andparticularly preferably 0.12% (w/v) or 0.15% (w/v). In the case ofbimatoprost, it is preferably 0.0001 to 5% (w/v), more preferably 0.001to 1% (w/v), further preferably 0.01 to 0.03% (w/v), and particularlypreferably 0.01% (w/v) or 0.03% (w/v). In the case of travoprost, it ispreferably 0.0001 to 5% (w/v), more preferably 0.001 to 1% (w/v), andparticularly preferably 0.004% (w/v).

Incidentally, when the other prophylactic or therapeutic agent(s) forglaucoma or ocular hypertension is in the form of a salt, a hydrate or asolvate, the content of the other prophylactic or therapeutic agent(s)for glaucoma or ocular hypertension may be calculated based on any of afree form, a salt, a hydrate or a solvate of the other prophylactic ortherapeutic agent(s) for glaucoma or ocular hypertension.

In the therapeutic agent or the like of the present invention, in placeof the Rho-associated coiled-coil containing protein kinaseinhibitor(s), one or more of the other prophylactic or therapeuticagent(s) for glaucoma or ocular hypertension may be used in combinationwith sepetaprost. As the other prophylactic or therapeutic agent(s) forglaucoma or ocular hypertension, any substance may be used, as long asit has an intraocular pressure lowering action or a neuroprotectiveaction and is useful for the treatment for glaucoma, there may bementioned non-selective sympathomimetics, α₂ receptor agonists, α₁receptor blockers, parasympathomimetics, carbonic anhydrase inhibitors,prostaglandins, NMDA antagonists, and the like, and specific examplesthereof or contents thereof are as described above. As examples of morespecific combination, there may be mentioned a combination ofsepetaprost and dipivefrin, a combination of sepetaprost andbrimonidine, a combination of sepetaprost and apraclonidine, acombination of sepetaprost and bunazosin, a combination of sepetaprostand pilocarpine, a combination of sepetaprost and carbachol, acombination of sepetaprost and demecarium, a combination of sepetaprostand echothiphate, a combination of sepetaprost and distigmine bromide, acombination of sepetaprost and dorzolamide, a combination of sepetaprostand brinzolamide, a combination of sepetaprost and acetazolamide, acombination of sepetaprost and diclofenamide, a combination ofsepetaprost and methazolamide, a combination of sepetaprost andisopropyl unoprostone, a combination of sepetaprost and latanoprost, acombination of sepetaprost and travoprost, and a combination ofsepetaprost and bimatoprost.

The therapeutic agent or the like of the present invention ischaracterized in that sepetaprost and the Rho-associated coiled-coilcontaining protein kinase inhibitor(s) are administered in combinationwhereby glaucoma or ocular hypertension is to be prevented or treated.As the glaucoma in the therapeutic agent or the like of the presentinvention, primary open-angle glaucoma, secondary open-angle glaucoma,normal tension glaucoma, hypersecretion glaucoma, primary angle-closureglaucoma, secondary angle-closure glaucoma, plateau iris glaucoma,combined-mechanism glaucoma, developmental glaucoma, steroid inducedglaucoma, exfoliation glaucoma, amyloid glaucoma, neovascular glaucoma,malignant glaucoma, capsular glaucoma of the lens, plateau iris syndromeand the like are exemplified.

In the therapeutic agent or the like of the present invention, as forthe dosage form, a formulation comprising sepetaprost, and a separateformulation comprising the Rho-associated coiled-coil containing proteinkinase inhibitor(s) may be administered (concomitant administration), ora single formulation (combination drug) comprising sepetaprost and theRho-associated coiled-coil containing protein kinase inhibitor(s) may beadministered. Also, when one or more of the other prophylactic ortherapeutic agent(s) for glaucoma or ocular hypertension is used incombination in addition to sepetaprost and the Rho-associatedcoiled-coil containing protein kinase inhibitor(s), then, sepetaprostand the Rho-associated coiled-coil containing protein kinaseinhibitor(s), and the other prophylactic or therapeutic agent(s) forglaucoma or ocular hypertension may be administered concomitantly, acombination drug comprising optional component(s) of these and theremaining component(s) may be administered concomitantly, or acombination drug comprising all the components may be administered.

The therapeutic agent or the like of the present invention may beadministered orally or parenterally, no particular technique is requiredfor formulation thereof, and a formulation can be prepared by using acommonly used technique. As dosage forms, there may be mentioned eyedrops, eye ointments, injections, tablets, capsules, granules, powdersand the like, and eye drops or eye ointments are preferred.

When sepetaprost and the Rho-associated coiled-coil containing proteinkinase inhibitor(s), and the other prophylactic or therapeutic agent(s)for glaucoma or ocular hypertension are separately formulated,formulations can be each prepared according to the known method. As aformulation of the Rho-associated coiled-coil containing protein kinaseinhibitor(s) or the other prophylactic or therapeutic agent for glaucomaor ocular hypertension, formulations already commercially available suchas ripasudil, netarsudil, dipivefrin, brimonidine, apraclonidine,bunazosin, timolol, befunolol, carteolol, nipradilol, betaxolol,levobunolol, metipranolol, pilocarpine, dorzolamide, brinzolamide,acetazolamide, isopropyl unoprostone, latanoprost, travoprost,bimatoprost, Cosopt (Registered Trademark) combination eye drops,Xalacom (Registered Trademark) combination eye drops, DuoTrav(Registered Trademark) combination eye drops and the like or asubstance(s) corresponding to these may be also used.

Also, when one formulation containing the respective components is to beprepared, it can be prepared according to a known method.

In the case of preparing eye drops, sepetaprost and the Rho-associatedcoiled-coil containing protein kinase inhibitor(s) are added to purifiedwater, a buffer solution or the like, and stirred, and then, a pH of themixture is adjusted with a pH adjusting agent to prepare a desired eyedrop. In addition, if necessary, an additive(s) commonly used in eyedrops may be used, and as the additives, there may be mentioned anisotonic agent, a buffering agent, a surfactant, a stabilizer, apreservative, a solubilizing agent, and the like.

A pH of the eye drops may be within the range which is allowable forophthalmic formulations, it is preferably in the range of pH 4 to 8, andmore preferably in the range of pH 5 to 7.

In the case of preparing eye ointments, it can be prepared by using acommonly used base, and as the base, there may be mentioned whitepetrolatum, liquid paraffin, and the like.

In the case of preparing oral formulations such as tablets, capsules,granules, powders, and the like, it can be prepared by adding a bulkingagent, a lubricant, a binder, a disintegrating agent, a coating agent, afilm agent, and the like, as necessary. As the bulking agent, there maybe mentioned lactose, crystalline cellulose, starch, vegetable oil, andthe like, as the lubricant, there may be mentioned magnesium stearate,talc, and the like, as the binder, there may be mentioned hydroxypropylcellulose, polyvinylpyrrolidone, and the like, as the disintegratingagent, there may be mentioned carboxymethylcellulose calcium,low-substituted hydroxypropylmethyl cellulose, and the like, as thecoating agent, there may be mentioned hydroxypropyl methylcellulose,macrogol, silicone resin, and the like, and as the film agent, there maybe mentioned a gelatin film, and the like.

An administration method of the therapeutic agent or the like of thepresent invention can be appropriately changed depending on the dosageform, the severity of symptoms of a patient to be administered to, theage, the body weight, the administration route, the judgment of adoctor, and the like, and in the case of a combination drug comprisingsepetaprost and a Rho-associated coiled-coil containing protein kinaseinhibitor(s), it may be administered 1 to 5 times a day, preferably onceor twice a day, and most preferably once a day. When a formulationcomprising sepetaprost and a formulation comprising a Rho-associatedcoiled-coil containing protein kinase inhibitor(s) are administeredconcomitantly, each formulation may be administered at different timesor simultaneously 1 to 3 times a day, preferably once or twice a day,and most preferably once a day. Incidentally, in the concomitantadministration, when the formulations are administered at differenttimes, the order of administering the formulations is not limited, andafter one formulation is administered, the other formulation may beadministered within 12 hours, preferably within 6 hours, more preferablywithin 1 hour, further preferably within 30 minutes, particularlypreferably within 5 minutes, and most preferably promptly. In theabove-mentioned administration method, in the case of eye dropadministration, it is preferable to administer 1 to 3 drops per once,more preferably to administer 1 or 2 drops, and most preferably toadminister 1 drop.

The detailed description of the above-mentioned therapeutic agent or thelike of the present invention is also applied to the prophylactic ortherapeutic agent for glaucoma or ocular hypertension comprisingsepetaprost of the present invention, which is characterized by beingused concomitantly with a Rho-associated coiled-coil containing proteinkinase inhibitor(s). The detailed description of the above-mentionedtherapeutic agent or the like of the present invention is also appliedto an intraocular pressure-lowering agent of the present invention,which is characterized in that sepetaprost and a Rho-associatedcoiled-coil containing protein kinase inhibitor(s) are combined. Thedetailed description of the above-mentioned therapeutic agent or thelike of the present invention is also applied to an intraocularpressure-lowering agent of the present invention comprising sepetaprost,which is characterized by being used concomitantly with a Rho-associatedcoiled-coil containing protein kinase inhibitor(s).

Also, detailed description of the above-mentioned therapeutic agent orthe like of the present invention is also applied to the embodiment ofthe present invention mentioned below.

One embodiment of the present invention is a composition for theprophylaxis or treatment for glaucoma or ocular hypertension comprisingsepetaprost, which is characterized by being administered in combinationwith a Rho-associated coiled-coil containing protein kinaseinhibitor(s).

One embodiment of the present invention is a prophylactic or therapeuticmethod for glaucoma or ocular hypertension comprising: administering atherapeutically effective amount of sepetaprost, and a therapeuticallyeffective amount of a Rho-associated coiled-coil containing proteinkinase inhibitor(s) in combination to a subject in need thereof.

One embodiment of the present invention is use of a combination ofsepetaprost and a Rho-associated coiled-coil containing protein kinaseinhibitor(s) for manufacturing a medicament for the prophylaxis ortreatment for glaucoma or ocular hypertension.

One embodiment of the present invention is use of sepetaprost formanufacturing a medicament for the prophylaxis or treatment for glaucomaor ocular hypertension, which characterized by being used concomitantlywith a Rho-associated coiled-coil containing protein kinaseinhibitor(s).

One embodiment of the present invention is sepetaprost for use in theprophylaxis or treatment for glaucoma or ocular hypertension, which ischaracterized by being used concomitantly with a Rho-associatedcoiled-coil containing protein kinase inhibitor(s).

One embodiment of the present invention is a combination of sepetaprostand a Rho-associated coiled-coil containing protein kinase inhibitor(s)for use in the prophylaxis or treatment for glaucoma or ocularhypertension.

One embodiment of the present invention is a composition for lowering anintraocular pressure comprising sepetaprost, which is characterized bybeing administered in combination with a Rho-associated coiled-coilcontaining protein kinase inhibitor(s).

One embodiment of the present invention is a method for lowering anintraocular pressure comprising: administering a therapeuticallyeffective amount of sepetaprost, and a therapeutically effective amountof a Rho-associated coiled-coil containing protein kinase inhibitor(s)to a subject in need thereof.

One embodiment of the present invention is use of a combination ofsepetaprost and a Rho-associated coiled-coil containing protein kinaseinhibitor(s) for manufacturing a medicament for lowering an intraocularpressure.

One embodiment of the present invention is use of sepetaprost formanufacturing a medicament for lowering an intraocular pressurecharacterized by being used concomitantly with a Rho-associatedcoiled-coil containing protein kinase inhibitor(s).

One embodiment of the present invention is sepetaprost for use inlowering an intraocular pressure, which is characterized by being usedconcomitantly with a Rho-associated coiled-coil containing proteinkinase inhibitor(s).

One embodiment of the present invention is a combination of sepetaprostand a Rho-associated coiled-coil containing protein kinase inhibitor(s)for use in lowering an intraocular pressure.

EXAMPLES

In the following, results of pharmacological tests are shown, but theseare for better understanding of the present invention and do not limitthe scope of the present invention.

[Pharmacological Test]

Example 1

In order to examine usefulness of the combination of sepetaprost and aRho-associated coiled-coil containing protein kinase inhibitor(s), theeffect of lowering an intraocular pressure when sepetaprost andripasudil which is a Rho-associated coiled-coil containing proteinkinase inhibitor were administered concomitantly to experimental animals(normal pressure monkeys) was investigated.

(Preparation of Compound Solutions to be Tested)

(1) Preparation of Sepetaprost Solution

Sepetaprost was dissolved in purified water containing a solubilizingagent, and then, a sepetaprost solution with a desired concentration wasprepared by using a commonly used method.

(2) Preparation of Ripasudil Solution

Commercially available ripasudil eye drop (Kowa Company, Ltd., GLANATEC(Registered Trademark) eye drops 0.4%) was used as it was.

(Test Method)

An effect of lowering an intraocular pressure when sepetaprost andripasudil were administered concomitantly was investigated. As acomparative subject, an effect of lowering an intraocular pressure whensepetaprost or ripasudil was administered alone was also investigated.As a control, the base of the sepetaprost solution and physiologicalsaline solution were administered.

(Drugs and Animals Used in the Test)

Sepetaprost solution: 0.0003% (w/v) sepetaprost solution (volume of eyedropped: 20 μL/eye)

Ripasudil solution: 0.4% (w/v) ripasudil solution (trade name: GLANATEC(Registered Trademark) eye drops 0.4%, volume of eye dropped: 20 μL/eye)

Experimental animal: cynomolgus monkey (sex: male, 8 monkeys per agroup)

(Administration Method and Measurement Method)

[1] Concomitant Administration of Sepetaprost and Ripasudil

(1) A drop of 0.4% oxybuprocaine hydrochloride eye drop (trade name:Benoxil (Registered Trademark) eye drops 0.4%) was applied to one eye ofan experimental animal and local anesthesia was conducted.

(2) Immediately before administration of a compound solution to betested, an intraocular pressure was measured and the value was made anintraocular pressure (0 hour) before administration.

(3) The sepetaprost solution was applied to one eye of an experimentalanimal (the contralateral eye was untreated). After a short time (afterabout 5 minutes), the ripasudil solution was applied to the same eye.

(4) After 2 hours, 4 hours, 6 hours, 8 hours and 24 hours from applyingthe sepetaprost solution to the eye, one drop of 0.4% oxybuprocainehydrochloride eye drop was applied to the eye to be measured for theintraocular pressure respectively, and after local anesthesia, theintraocular pressure was measured. Also, the intraocular pressure wasmeasured each three times, and the average value was calculated. Withrespect to the changed value of the intraocular pressure (mmHg), adifference from the value of the intraocular pressure beforeadministration at each measurement time point was calculated.

[2] Single Administration of Sepetaprost

The test was carried out in the same manner as the above-mentionedconcomitant administration test except for changing the ripasudilsolution to the physiological saline solution.

[3] Single Administration of Ripasudil

The test was carried out in the same manner as the above-mentionedconcomitant administration test except for changing the sepetaprostsolution to the base of the sepetaprost solution.

[4] Control

The test was carried out in the same manner as the above-mentionedconcomitant administration test except for changing the sepetaprostsolution to the base of the sepetaprost solution and changing theripasudil solution to the physiological saline solution.

(Results)

The changes in the lowering of the intraocular pressure with the lapseof time for each administered group are shown in FIG. 1 and Table 1. Thechanges in the intraocular pressure values are shown by an averagevalue±SEM of the difference from the value (0 hour) beforeadministration of eight monkeys in each group with regard to eachmeasurement time point of each individual. Comparison of the controlgroup with the sepetaprost group, the ripasudil group, or thesepetaprost/ripasudil concomitant use group, and comparison of thesepetaprost/ripasudil concomitant use group with the sepetaprost groupor the ripasudil group was carried out by, after carrying out theBartlett test, in the case where dispersion is uniform, using theDunnett test, or in the case of ununiform, using the Steel test. Thesignificance level with respect to the control group was shown as ##:p<0.01 in the Dunnett test, and *: p<0.05 and **: p<0.01 in the Steeltest. The significance level with respect to the sepetaprost/ripasudilconcomitant group was shown as †: p<0.05 and ††: p<0.01 in the Dunnetttest, and $$: p<0.01 in the Steel test.

TABLE 1 Time after dropping 2 4 6 8 24 Control 0.0 −0.2 −0.2 −0.1 0.0Sepetaprost −0.1 −0.9 −1.8 −1.9 −0.6 Ripasudil −2.4 −1.8 −1.6 −1.5 −0.4Sepetaprost/ripasudil −3.0 −3.5 −3.4 −3.8 −0.7 concomitant use

As clearly seen from FIG. 1 and Table 1, the concomitantly administeredgroup of sepetaprost and ripasudil showed more excellent intraocularpressure lowering action and sustained effect of the action than thesingle drug administered group, that is, the sepetaprost administeredgroup and the ripasudil administered group. In particular, at 2, 4 and 8hours after administration, the amounts of change in the intraocularpressure values for the concomitantly administered group of sepetaprostand ripasudil was larger than the sum of the amounts of change in theintraocular pressure values for the sepetaprost administered group andfor the ripasudil administered group, and the synergistic effect of theintraocular pressure lowering action was confirmed.

From the above, it was found that by combining sepetaprost with aRho-associated coiled-coil containing protein kinase inhibitor(s), morepotent intraocular pressure lowering action and a sustained effect ofthe action can be obtained.

Example 2

In order to examine usefulness of the combination of sepetaprost and aRho-associated coiled-coil containing protein kinase inhibitor(s), theeffect of lowering an intraocular pressure when sepetaprost andnetarsudil which is a Rho-associated coiled-coil containing proteinkinase inhibitor were administered concomitantly to experimental animals(normal pressure monkeys) was investigated.

(Preparation of Compound Solutions to be Tested)

(1) Preparation of Sepetaprost Solution

Sepetaprost was dissolved in purified water containing a solubilizingagent, and then, a sepetaprost solution with a desired concentration wasprepared by using a commonly used method.

(2) Preparation of Netarsudil Solution

Dimesylate of netarsudil was dissolved in a physiological salinesolution containing a solubilizing agent, and then, a netarsudilsolution having a desired concentration was prepared by using a commonlyused method.

(Test Method)

An effect of lowering an intraocular pressure when sepetaprost andnetarsudil were administered concomitantly was investigated. As acomparative subject, an effect of lowering an intraocular pressure whensepetaprost or netarsudil was administered alone was also investigated.As a control, the base of the sepetaprost solution and the base of thenetarsudil solution were administered.

(Drugs and Animals Used in the Test)

Sepetaprost solution: 0.0003% (w/v) sepetaprost solution (volume of eyedropped: 20 μL/eye)

Netarsudil solution: 0.01% (w/v) netarsudil solution (volume of eyedropped: 20 μL/eye)

Experimental animal: cynomolgus monkey (sex: male, 8 monkeys per agroup)

(Administration Method and Measurement Method)

[1] Concomitant Administration of Sepetaprost and Netarsudil

(1) A drop of 0.4% oxybuprocaine hydrochloride eye drop (trade name:Benoxil (Registered Trademark) eye drops 0.4%) was applied to one eye ofthe experimental animal and local anesthesia was conducted.

(2) Immediately before administration of a compound solution to betested, an intraocular pressure was measured and the value was made anintraocular pressure (0 hour) before administration.

(3) The sepetaprost solution was applied to one eye of the experimentalanimal (the contralateral eye was untreated). After a short time (afterabout 5 minutes), the netarsudil solution was applied to the same eye.

(4) After 2 hours, 4 hours, 6 hours, 8 hours and 24 hours from applyingthe sepetaprost solution to the eye, one drop of 0.4% oxybuprocainehydrochloride eye drop was applied to the eye to be measured for theintraocular pressure respectively, and after local anesthesia, theintraocular pressure was measured. Also, the intraocular pressure wasmeasured each three times, and the average value was calculated. Withrespect to the changed value of the intraocular pressure (mmHg), adifference from the value of the intraocular pressure beforeadministration at each measurement time point was calculated.

[2] Single Administration of Sepetaprost

The test was carried out in the same manner as the above-mentionedconcomitant administration test except for changing the netarsudilsolution to the base of the netarsudil solution.

[3] Single Administration of Netarsudil

The test was carried out in the same manner as the above-mentionedconcomitant administration test except for changing the sepetaprostsolution to the base of the sepetaprost solution.

[4] Control

The test was carried out in the same manner as the above-mentionedconcomitant administration test except for changing the sepetaprostsolution to the base of the sepetaprost solution and changing thenetarsudil solution to the base of the netarsudil solution.

(Results)

The changes in the lowering of the intraocular pressure with the lapseof time for each administered group are shown in FIG. 2 and Table 2. Thechange in the intraocular pressure values are shown by an averagevalue±SEM of the difference from the value (0 hour) beforeadministration of eight monkeys in each group with regard to eachmeasurement time point of each individual. Comparison of the controlgroup with the sepetaprost group, the netarsudil group, or thesepetaprost/netarsudil concomitant use group, and comparison of thesepetaprost/netarsudil concomitant use group with the sepetaprost groupor the netarsudil group was carried out by, after carrying out theBartlett test, in the case where dispersion is uniform, using theDunnett test, or in the case of ununiform, using the Steel test. Thesignificance level with respect to the control group was shown as *:p<0.05 and **: p<0.01 in the Steel test, and *: #: p<0.05 and ###:p<0.001 in the Dunnett test. The significance level with respect to thesepetaprost/netarsudil concomitant use group was shown as †: p<0.05 inthe Dunnett test.

TABLE 2 Time after dropping 2 4 6 8 24 Control 0.2 0.0 −0.1 −0.3 0.0Sepetaprost −0.2 −1.6 −2.2 −2.0 −1.1 Netarsudil −0.4 −2.2 −2.1 −2.3 −0.6Sepetaprost/netarsudil −0.3 −3.0 −3.2 −3.9 −1.1 concomitant use

As clearly seen from FIG. 2 and Table 2, the concomitantly administeredgroup of sepetaprost and netarsudil showed more excellent intraocularpressure lowering action and sustained effect of the action than thesingle drug administered group, that is, the sepetaprost administeredgroup and the netarsudil administered group.

From the above, it was found that by combining sepetaprost with aRho-associated coiled-coil containing protein kinase inhibitor(s), morepotent intraocular pressure lowering action and a sustained effect ofthe action can be obtained.

INDUSTRIAL APPLICABILITY

When sepetaprost and a Rho-associated coiled-coil containing proteinkinase inhibitor(s) are combined and administered to the eye, anintraocular pressure lowering action is enhanced. Therefore, the presentinvention is useful as a prophylactic or therapeutic agent for glaucomaor ocular hypertension.

1. A prophylactic or therapeutic agent for glaucoma or ocularhypertension, wherein sepetaprost and a Rho-associated coiled-coilcontaining protein kinase inhibitor(s) are administered in combination.2. The prophylactic or therapeutic agent according to claim 1, which isa combination drug comprising sepetaprost and the Rho-associatedcoiled-coil containing protein kinase inhibitor(s).
 3. The prophylacticor therapeutic agent according to claim 1, wherein sepetaprost and theRho-associated coiled-coil containing protein kinase inhibitor(s) areadministered at different times or simultaneously.
 4. A prophylactic ortherapeutic agent for glaucoma or ocular hypertension comprisingsepetaprost, which is used concomitantly with a Rho-associatedcoiled-coil containing protein kinase inhibitor(s).
 5. The prophylacticor therapeutic agent according to claim 4, which is administered atdifferent time from or simultaneously with the Rho-associatedcoiled-coil containing protein kinase inhibitor(s).
 6. The prophylacticor therapeutic agent according to claim 1, wherein the Rho-associatedcoiled-coil containing protein kinase inhibitor(s) is at least one kindselected from the group consisting of ripasudil, netarsudil and a saltthereof.
 7. The prophylactic or therapeutic agent according to claim 1,wherein the Rho-associated coiled-coil containing protein kinaseinhibitor(s) is ripasudil monohydrochloride dihydrate.
 8. Theprophylactic or therapeutic agent according to claim 1, wherein theRho-associated coiled-coil containing protein kinase inhibitor(s) isdimesylate or dihydrochloride of netarsudil.
 9. A prophylactic ortherapeutic method for glaucoma or ocular hypertension comprising:administering a therapeutically effective amount of sepetaprost and atherapeutically effective amount of a Rho-associated coiled-coilcontaining protein kinase inhibitor(s) to a subject in need thereof. 10.The prophylactic or therapeutic method for glaucoma or ocularhypertension according to claim 9, wherein sepetaprost and theRho-associated coiled-coil containing protein kinase inhibitor(s) areadministered as a combination drug.
 11. The prophylactic or therapeuticmethod for glaucoma or ocular hypertension according to claim 9, whereinsepetaprost and the Rho-associated coiled-coil containing protein kinaseinhibitor(s) are administered at different times or simultaneously. 12.The prophylactic or therapeutic method for glaucoma or ocularhypertension according to claim 9, wherein the Rho-associatedcoiled-coil containing protein kinase inhibitor(s) is at least one kindselected from the group consisting of ripasudil, netarsudil and a saltthereof.
 13. The prophylactic or therapeutic method for glaucoma orocular hypertension according to claim 9, wherein the Rho-associatedcoiled-coil containing protein kinase inhibitor(s) is ripasudilmonohydrochloride dihydrate.
 14. The prophylactic or therapeutic methodfor glaucoma or ocular hypertension according to claim 9, wherein theRho-associated coiled-coil containing protein kinase inhibitor(s) isdimesylate or dihydrochloride of netarsudil.